These studies were designed to investigate the effect of calcium channel blockers on chemically-induced gastric lesions in rats. Results of this study indicated that pretreatment of male F344 rats with the calcium channel blockers verapamil, diltiazem, or Mg++ significantly protected against ethanol- and indomethacin-induced gastric lesions as demonstrated by gross and histopathologic evaluation. Treatment of rats with calcium channel blockers prior to ethanol or indomethacin resulted in a significant decline in the mean number of lesions per glandular stomach, the damaged area of the glandular stomach and the severity of lesions. Calcium channel blockers also caused a significant decline in the incidence of indomethacin-induced gastric lesions, but had no effect on the incidence of ethanol-induced gastric lesions. These results offer the first evidence that calcium channel blockers may play an important role in protection against chemically-induced gastric lesions and thereby offer insight into the mechanism of gastric ulcer formation.